Background and objectives: Muscle wasting, a common complication in chronic kidney disease (CKD), contributes to poor outcomes. Mitochondrial biogenesis is critical for the maintenance of skeletal muscle function and structural integrity. The present study-a secondary analysis from a published randomized controlled trial-examined the effect of resistance exercise training on skeletal muscle mitochondrial (mt)DNA copy number and determined its association with skeletal muscle phenotype (muscle mass and strength).Design, setting, participants, & measurements: Twenty-three patients with moderate-to-severe CKD were randomized to resistance training (n ‫؍‬ 13) or an attention-control (n ‫؍‬ 10) group for 12 weeks. After a run-in period of a low-protein diet that continued during the intervention, mtDNA copy number in the vastus lateralis muscle was estimated by quantitative real-time PCR at baseline and 12 weeks.Results: Participants mean age was 64 ؎ 10 (SD) years and median (interquartile range, IQR) GFR 27.5 (37.0) ml/min. There were no differences between groups at baseline. Median (IQR) mtDNA copy number was 13,713 (10,618). There was a significant increase in muscle mtDNA with exercise compared with controls (1306 [13306] versus ؊3747 [15467], P ‫؍‬ 0.01). The change in muscle mtDNA copy number was positively correlated with previously reported changes in types I and II muscle fiber cross-sectional area.Conclusions: In this pilot study, resistance training was highly effective in enhancing mitochondrial content in patients with moderate-to-severe CKD. This finding suggests that the mitochondrial dysfunction observed with chronic disease could potentially be restored with this exercise modality and should be investigated further.